HIV reservoirs pose significant treatment obstacles and provide a continuing source of genetically diverse, replication-competent virus to perpetuate disease. A major human reservoir of HIV is the follicular dendritic cell (FDC) network, which harbors genetically diverse virus including archived drug-resistance quasispecies that are not found elsewhere. FDCs are confined to the follicles of secondary lymphoid tissues (sLTs) where they trap and retain HIV extracellularly in the form of immune complexes (ICs) comprised of specific antibody (Ab) and/or complement (C') components. FDCs trap ICs (including HIV) using CD32 (Fc?RIIB) and CD21 (Complement Receptor 2), although other as yet unknown receptors may also make contributions in the case of HIV-IC. FDC-trapped HIV is highly infectious and remarkably, remains so even in the presence of high concentrations of neutralizing antibodies (NtAb). Moreover, FDC virus infectivity persists for months to years in the absence of ongoing infection and/or replication. FDCs also produce TNFa (and likely other cytokines) that increases NF?B activation and in turn, HIV replication and contributes to the highly activated state of cells in the germinal center (GC), including CD4+ GC T cells that are frequently infected. The importance of the FDC-HIV reservoir is supported by the observation that active virus replication persists surrounding FDCs throughout the natural course of disease. FDCs are now known to exist in two states, activated and resting. The objective of this proposed research is to determine if activation of FDCs is required: 1) to maintain HIV infectivity over time, 2) to increase HIV expression in infected cells, and 3) to transmit infection in the presence of potent neutralizing antibodies. A better understanding of the FDC reservoir of highly infectious HIV can permit the design of specific intervention strategies that can target this dangerous repository of HIV. PUBLIC HEALTH RELEVANCE: Follicular dendritic cells (FDCs) represent a large, but understudied reservoir of infectious HIV that can contribute to persisting infection. This application focuses on the role of FDC activation upon this cell's ability to maintain the infectious nature of HIV trapped on its surfaces, increase virus expression in CD4+ T cells and transmit infection in the presence of potent neutralizing antibodies. Understanding how the FDC interacts with HIV and how this can be controlled can provide the ability to block this dangerous reservoir of infectious virus.